Contrast Nephropathy—The Clinical Problem
With the increasing use of radiographic contrast media in diagnostic and interventional procedures, contrast-induced nephropathy (CN) has become an important cause of acute renal impairment. While CN rarely (less than 1% of cases) results in permanent renal failure, CN in any form, results in a significantly increased overall cost to the hospital from prolonged admissions to observe and/or treat while awaiting the return of the patient's pre-CN baseline renal function.
Even in its milder forms, CN can increase the time that patients remain in the hospital by 3-5 days. The more severe the CN, the longer the increase in hospital stay. In those patients who require short-term dialysis (even though their kidneys eventually return to their pre-CN baseline), the hospital stay made be increased by 2-4 weeks due to CN.
The Properties, Use and Effects of Contrast Media
Radiographic contrast agents can be grouped into two main categories: positive contrast agents and negative contrast agents. Positive contrast media are radiopaque (appearing lighter than surrounding structures) due to their ability to attenuate the X-ray beam. Positive contrast agents contain elements with high atomic weights, (such as iodine, bromine, and barium) which add density to the tissues of interest. Negative contrast agents are radiolucent (darker than surrounding structures) because of their inability to attenuate the X-ray beam. Air and water are examples of negative contrast agents.
Intravenous contrast agents are used to help highlight blood vessels and to enhance the tissue structure of various organs such as the brain, spine, liver and kidneys. Intravenous contrast is clear like water and has a similar consistency. It is typically packaged in glass bottle or vial. A sterile syringe is used to draw it from the bottle or a power injector is used to administer the contrast. Typically between 75 cc to 150 cc (about 2.5 oz. to 5 oz) of contrast is injected depending upon the patient's age, weight, area being imaged and cardiovascular health.
Types of Intravascular Contrast Media
Intravascular contrast agents typically comprise iodinated benzene ring derivatives that are formulated as sodium or megiumine salts. The multiple iodine molecules contained within the contrast agent are responsible for the X-ray attenuation. The amount of radiopacity that is generated by a particular contrast agent is a function of the percentage of iodine in the molecule and the concentration of the contrast media administered. The iodine content in different radiographic contrast media can vary from 11% to 48%.). Iodinated contrast agents are classified as ionic or high osmolar contrast media (HOCM) or nonionic or low osmolar contrast media (LOCM).
Ionic (HOCM)
Ionic contrast media dissociate into separate particles, or ions, when placed in water solutions. An ion is an atom or group of atoms that carries a positive or negative charge. The dissociation of the molecules in ionic contrast media is responsible for its increased osmolality in the blood in comparison to nonionic contrast media. Ionic media breakdown into cations, positively charged particles and anions, negatively charged particles. For every three iodine molecules present in an ionic media, one cation and one anion are produced when it enters a solution. Ionic contrast media are generally referred to as 3:2 compounds. The cations and anions are the direct result of the disassociation of compounds that are attached as “side chains” to the contrast media molecule. Sodium and/or meglumine are cations and diatrizoate and iothalamate are the common anions. Human blood has an osmolality of approximately 300 milliosmoles (mOsm) per kilogram (kg) or 30 mOsm per deciliter (or 30%), while a typical ionic contrast agent can have an osmolality on the order of 1300 mOsm/kg to 1600 mOsm/kg or 130 mOsm per deciliter, making it a hypertonic solution with respect to blood.
Nonionic (LOCM)
Unlike ionic contrast media, the nonionic contrast media do not dissociate into ions, thus resulting in a lower osmolality contrast agent. Non-ionic contrast media do not dissolve into charged particles when it enters a solution. For every three iodine molecules in a non-ionic solution, one neutral molecule is produced. Non-ionic contrast media are referred to as 3:1 compounds. Typical nonionic contrast agents have an osmolality on the order of 500 mOsm/kg to 850 mOsm/kg or 50 mOsm per deciliter to 85 mOsm per deciliter. Although their osmolality is lower than ionic contrast media, they are still considered hypertonic with respect to blood.
The low-osmolality contrast media are represented structurally by the ionic dimers, nonionic monomers, and nonionic dimers. Ioxaglate is the only commonly used ionic dimer. In solution it forms two particle aggregates and does not readily ionize, rendering an osmolality of about 600 mOsm/kg H2O. The nonionic monomers, as a result of their lower toxicities, are rapidly becoming the contrast agents of choice. In addition to nonionic tendencies and lower osmolalities, the newer nonionic monomers, such as ioversol and iohexal, are more hydrophilic and thus potentially less chemotoxic. The approximate osmolality range of these agents is 290 to 860 mOsm/kg H2O. The lower toxicity of LOCM is offset somewhat by higher cost. The nonionic dimers are largely in the developmental stages. Although the osmolality of these agents approaches that of plasma, they are highly viscous and thus of limited clinical usefulness. When evaluating the literature, one must note the potential differences in the terms ionic, nonionic, and low osmolality, high osmolality. Ioxaglate is an LOCM, but it also has some ionic tendencies.
The osmolality of a solution is the measurement of the number of molecules and particles in a solution per kilogram of water. An injection of contrast media, especially ionic HOCM, results in a big increase in the number of particles contained in the vascular system. The introduction of contrast media into the vascular system causes water from intracellular place to move into the intravascular space in an attempt to equalize concentrations. The blood vessels dilate in an attempt to compensate from the increased fluid volume. If the fluid shift is too large, fluid will transudates into the surrounding tissues resulting is such conditions as pulmonary edema.
How is Intravenous Contrast Used
An intravenous needle is first placed into a vein in the hand or arm. Once the needle is in place, the vein is flushed with saline solution. The contrast may be hand injected using a large syringe connected to the needle via tubing or via a power-assisted injector. After the iodine contrast has been injected, e.g., as a bolus, into the blood stream, it circulates through the heart and passes into the arteries, through the body's capillaries and then into the veins and back to the heart. The x-ray beam is attenuated as they pass through the blood vessels and organs containing contrast. This causes the blood vessels and organs filled with the contrast to “enhance” and show up as white areas on the x-ray or CT (computed tomography) images. The kidneys and liver eliminate the contrast from the blood.
There are three phases of intravascular contrast enhancement: bolus or arterial phase, non-equilibrium or venous phase, and the equilibrium or portal phase. The bolus phase represents the critical time of peak enhancement within the target vessel or organ and occurs immediately after the injection of contrast and lasts between 10 seconds and 60 seconds postinfusion depending on the amount and site of injection. For coronary angiography, a 5 cc bolus into the coronary artery will last much shorter than a 70 cc bolus into the left ventricle. The non-equilibrium phase occurs approximately 1 minute after the bolus of contrast media. The last phase is considered the equilibrium phase, which occurs approximately 2 minutes after the bolus injection. Thus, contrast becomes equally distributed in the total blood volume by about 2 minutes after a single injection.
On average, people at increased risk for contrast nephropathy receive less iodinated contrast material that those with normal renal function. The amount ranges from 250-300 cc in minimal to moderate renal insufficiency to as little as 50-70 cc in the highest risk patients.
Toxicity of Contrast Media
The toxicity of iodinated radiographic contrast media is related to (1) chemotoxicity, (2) ion toxicity, and (3) osmotoxicity of the specific compound used. Chemotoxicity increases as the hydrophobic nature of the substance increases. Chemotoxicity can result in release of vasoactive substances, activation of the complement and fibrinolytic systems, blockage of platelet aggregation, direct neurotoxicity, and decreased myocardial contractility and conduction. Ion toxicity is due to the direct effects of the anionic contrast medium or its conjugated cation on cellular membranes or cellular function. Osmotoxicity can result in pain upon injection, blood-brain barrier disruption, vagal and emetic center stimulation, decreased myocardial contractility, lowering of the myocardial fibrillation threshold, renal vasoconstriction, erythrocyte cell wall rigidity, increased pulmonary artery pressure, and decreased peripheral vascular resistance and vasodilation.
The so-called allergic reaction to iodinated radiographic contrast media is, in fact, an anaphylactoid or pseudoallergic reaction. Numerous mediators typical of allergic reactions are released or activated, but the mechanism is not antigen-antibody mediated. A true antibody-mediated reaction to iodinated radiographic contrast media is rare, with only three reported cases as of 1994. The exact mechanisms of these anaphylactoid reactions are not known but probably include direct cellular effects, direct enzyme induction, and direct activation of the compliment, fibrinolytic, kinin, and other systems. Symptoms usually develop within minutes of administration and reflect the actions of the released or activated mediating substances.
Potential Mechanisms of Contrast Nephropathy
The mechanisms of contrast nephropathy (CN) are not well understood. However, CN appears to be the result of a synergistic combination of direct renal tubular epithelial cell toxicity and renal medullary ischemia.
The injection of contrast induces a biphasic hemodynamic change in the kidney, with an initial, transient increase and then a more prolonged decrease in renal blood flow. Normal renal blood flow usually returns within 1 to 2 hours. The initial increased osmotic load of the contrast media triggers an intrarenal feedback resulting in renal arteriolar vasoconstriction. This phenomena is enhanced in salt-depleted or dehydrated animals. The mediators of these changes are still unknown. The renin-angiotensin system, calcium, prostaglandin, nitric oxide, endothelin and adenosine have been identified as possible mediators of this vasoconstriction.
Direct cytotoxicity in CN is suggested by histologic changes of cell injury and enzymuria after contrast administration. The nature of the contrast, associated ions, concentration, and concomitant hypoxia are all important to the degree of cellular damage, while the osmolality of the solution seems to be of secondary importance.
Definition and Clinical Features of CN
Renal dysfunction has been long recognized to be associated with the use of radiographic contrast media. The spectrum of dysfunction ranges from a transient slight increase in serum creatinine levels to overt renal failure requiring transient or long-term dialysis. Multiple definitions of CN, variations in the length of time serum creatinine is monitored, the different types, doses, and routes of contrast media used; and varying study designs have all resulted in a wide range of results and often conflicting conclusions and recommendations.
Mild, transient decreases in GFR occur after contrast administration in almost all patients. Whether a patient develops clinically significant acute renal failure, however, depends very much on the presence or absence of certain risk factors. Baseline renal impairment, diabetes mellitus, congestive heart failure, and higher doses of contrast media increase the risk of CN. Other risk factors include reduced effective arterial volume (e.g., due to dehydration, nephrosis, cirrhosis) or concurrent use of potentially nephrotoxic drugs such as nonsteroidal anti-inflammatory agents and angiotensin-converting enzyme inhibitors. Of all these risk factors, preexisting renal impairment appears to be the single most important; patients with diabetes mellitus and renal impairment, however, have a substantially higher risk of CN than patients with renal impairment alone.
Though many different definitions of CN appear in the literature, but it is commonly defined as an acute decline in renal function following the administration of intravenous contrast in the absence of other causes. Contrast nephropathy is commonly defined as the rise of 25% or more from the patient's baseline creatinine or a rise of at least 0.5 mg/dl. Patients with CN typically present with an acute rise in serum creatinine anywhere from 24 to 48 hours after the contrast study. Serum creatinine generally peaks at 3 to 5 days and returns to baseline value by 7 to 10 days.
The acute renal failure is nonoliguric in most cases. Urinalysis often reveals granular casts, tubular epithelial cells, and minimal proteinuria, but in many cases may be entirely bland. Most, but not all, patients exhibit low fractional excretion of sodium. The diagnosis of CN is frequently obvious if the typical course of events follows the administration of contrast. However, other causes of acute renal failure, including atheromatous embolic disease, ischemia, and other nephrotoxins should always be considered. This is particularly true if significant renal impairment should occur in patients without risk factors for CN.
Incidence of CN
Prospective studies have produced extremely varied estimates of the incidence of CN. These discrepancies are due to differences in the definition of renal failure as well as differences in patient comorbidity and the presence of other potential causes of acute renal failure. A recent epidemiologic study reported a rate of 14.5% in a series of approximately 1,800 consecutive patients undergoing invasive cardiac procedures. Patients without any significant risk factors have a much lower risk, averaging about 3% in prospective studies. On the other hand, the risk of renal failure after contrast rises with the number of risk factors present. In one study, the frequency of renal failure rose progressively from 1.2 to 100% as the number of risk factors went from zero to four.
Clinical Outcomes
The clinical importance of CN may not be immediately obvious given the high frequency of recovery of renal function, but it is by no means a benign complication. CN is no different from acute renal failure of any other etiology in terms of the complications that may ensue. Dialysis is infrequently required in approximately 0.7% of patients. Those who do require dialysis have very bad outcomes with a high mortality. Patients who don't require dialysis may still have increase in creatinine to 4-5 mg/dl. This reduction in renal function is clinically significant and may result in increase morbidity and mortality from delays in definitive therapies (such as coronary artery bypass surgery), need for alteration or increased toxicity of medications, delays in important diagnostic tests and longer total hospital stays. In addition, some degree of residual renal impairment has been reported in as many as 30% of those affected by CN. Other comorbid events such as hypotension, sepsis, and atheroembolic disease certainly contribute. Finally, there is some evidence that mortality may be increased in patients with CN. In a retrospective study, Levy et al. compared the outcomes of hospitalized patients with CN to a control group of patients matched for age, baseline serum creatinine, and type of diagnostic procedure that received contrast but did not develop CN. The mortality in the CN group was 34% compared with 7% in the control group (P<0.001, odds ratio 5.5), even when severity of comorbid illness was controlled by matching patients by APACHE II scores.
Previous Strategies Used to Prevent Contrast Nephropathy
Contrast administration, more often than not, is a planned procedure, and patients at particularly high risk can often be identified before the investigation. Renal impairment may be asymptomatic until advanced, but it is impractical to measure renal function before contrast administration in all cases. If no other risk factors for renal impairment are present, renal function is generally not assessed pre-study. When contrast administration is deemed appropriate, the lowest dose of contrast possible should be used. Optimally, any risk factors for CN should be corrected before contrast administration. If contrast must be administered in the presence of an uncorrectable or uncorrected risk factor, it is advisable to monitor renal function by serum creatinine before and at 48 to 72 h after the procedure.
A variety of specific measures have been used in an attempt to decrease the risk of CN, particularly in high-risk patients. The following is a discussion of the evidence supporting the use of some of the more common practices.
Fluid Administration
The administration of intravenous fluids has long been used to reduce the likelihood of CN for high-risk patients. The rationale for this approach is that giving fluids before the study may correct subclinical dehydration, whereas hydration for a period of time afterward may counter an osmotic diuresis resulting from the contrast. It is clear that even vigorous fluid administration does not afford complete protection from CN for high-risk patients. Even if only modestly beneficial, however, this approach is simple and carries minimal risks of adverse effects if appropriate care is taken, e.g., close monitoring of the patient's fluid balance and clinical status. However, use of this method in patients with Congestive Heart Failure or other fluid overload states in impractical.
Furosemide
The use of furosemide as prophylaxis for CN has been controversial. It has been hypothesized that loop diuretics might reduce the potential for ischemic injury by interfering with active transport and decreasing the oxygen demands of medullary tubular segments. Recent studies, however, suggest that furosemide may actually be detrimental in certain patients. There is currently more evidence arguing against rather than for the use of furosemide for the prophylaxis of CN, and its use for this purpose is not generally recommended.
Mannitol
Infusions of mannitol have also been widely used to prevent CN, but again its use is controversial. Overall, there is not enough evidence to recommend mannitol as a means to reduce CN.
Dopamine
Low-dose dopamine is a renal vasodilator and is effective even in patients with chronic renal insufficiency. This property has made it very attractive as a potential means for preventing CN, but clinical studies thus far have shown mixed results. Although it appears that dopamine may be of some benefit in preventing CN in nondiabetic patients, more evidence is required before it can be recommended for routine use. Dopamine should not be used to prevent CN in diabetic patients.
Atrial Natriuretic Peptide
Atrial natriuretic peptide (ANP) may theoretically interfere with the pathogenesis of CN by increasing renal blood flow, but clinical studies have not yet shown such a benefit. Based on available evidence, ANP cannot be recommended for prophylaxis of CN.
Calcium Channel Blockers
Drugs of this class have been shown to blunt the decreases in renal blood flow induced by contrast in laboratory studies. Several randomized trials of calcium-blocking agents for the prevention of CN have been published. However, the studies are quite small and do not include high-risk patients with renal insufficiency. Additional large-scale randomized trials are necessary, particularly in high-risk patients, before calcium channel blockers can be recommended for the prevention of CN. Patients taking calcium channel blockers for other indications, however, should continue their therapy uninterrupted.
Theophylline
Because adenosine has been suggested as having a role in the pathogenesis of CN, theophylline, an adenosine antagonist, has been investigated as a means to reduce the risk of this complication. Some studies have suggested that theophylline prevents some of the contrast-associated changes in renal function, but a benefit over saline hydration alone has not been convincingly demonstrated. This is particularly true with respect to patients with preexisting renal impairment. Nevertheless, there may be some value to the use of theophylline for reduction of CN in those at risk. Although the dose, duration, and route of administration of theophylline differed in each study, it seems likely that a dose of less than 5 mg/kg for less than 2 days, starting before contrast, is appropriate.
Current Strategies to Prevent Contrast Nephropathy
There are at least three current strategies, none of which have shown long-term proven benefit. Mucomyst is a drug that has shown some potential benefit. Iodixenol is purported to be a less toxic contrast agent though it is likely to be only an incremental benefit on existing diseases. Fenoldopam is a calcium-channel blocker made by Abbott that is supposed to increase renal blood flow. For each of these therapies, little significant clinical benefit has actually been shown. If at least equally effective, drug therapies are always preferred to device therapies. However, if none of these are proven to be clinically helpful, then there is a significant market for a novel device therapy.
Previous Use of Device Therapies to Reduce Contrast Concentrations in Blood
Hemodialysis and hemofiltration (artificial kidney) devices were used clinically in attempt to alter the contrast induced kidney damage. Clinically, these therapies have shown little sustained benefit. It is our belief that the longer the contrast is allowed to act on the kidney, the greater the potential for toxicity. What is not clear is 1) how soon the deleterious effects occur after contrast is injected and 2) whether removal of the contrast once damage has occurred is beneficial.
Some pre-clinical data is available to suggest that the higher the contrast dose and the longer the duration of exposure, the more significant the renal dysfunction. There have been no clinical trials that addressed the issue of essentially complete removal of contrast in less than two hours from the start of the procedure.
In view of the foregoing, there is a long felt need for a medical device that removes radiocontrast agents from the blood of a patient promptly after the injection of the agent. Interventional radiologists and cardiologists will use the technology during cardiac catheterization as well as potentially during other (e.g. AAA stenting, peripheral stenting, CT Scanning, or urology) procedures. There is a recognized problem associated with the use of intravenous radiocontrast medium (contrast) in the catheterization lab known as the radiocontrast induced nephropathy (RCN). Contrast can cause kidney damage. The clinical needs for a device to remove radiocontrast agents are:    1. To reduce the probability and severity of contrast nephropathy in the high-risk group of patients.    2. To allow the cardiologist or radiologist to use contrast more liberally during the procedure therefore making the procedure more effective and fast.    3. To make catheterization available to patients currently rejected because their kidneys are considered high risk.
Ideally the device shall be used by the catheter laboratory staff during the procedure and treatment terminated when the procedure is over. Treatment could continue for another hour after the procedure in the holding area.
The following are examples of the technical obstacles to clinical effective removal of radiocontrast from the bloodstream:    1. Modern nonionic contrast media molecules are small, non polarized and extremely hydrophilic (bind strongly to water). There are number of different chemical configurations. It is difficult to non-specifically separate contrast from plasma water.    2. Contrast media after injection does not stay in the blood but redistributes in the body fluid volume rapidly (within 15-20 minutes 50% redistribution level is reached). Total distribution volume of contrast in an average 70 kg person is on the order of 18-20 liters. In a larger person it can be significantly more. The consequence of this is that, if contrast is not removed before it is redistributed, the volume of body fluid that needs to be cleared of contrast increases from 2.5-3 liters of plasma water to 6 times that much. Since extracorporeal blood treatment can only clear plasma at a certain intrinsic rate, the duration of treatment required to achieve substantial clearance will increase proportionally.    3. Onset of damage to kidneys by contrast is quick. There are reasons to believe that some ischemic damage occurs after the kidney is exposed to contrast for 30-60 minutes. There is a belief that (a) prolonged exposure to contrast or (b) exposure to higher concentration of contrast exacerbates the damage to the kidneys. Reduction of renal injury by hydration of the patient supports the hypothesis that decreasing concentration of contrast in blood that reaches the kidney is beneficial. There is also proven increased risk of renal injury in cases where a larger amount of contrast was used. There is abundant clinical evidence that hydration of patients (infusion of up to 2 liters of fluid before, during and after the procedure) reduces the effect of contrast on renal function. This evidence suggests that by increasing the distribution volume and reducing the concentration of contrast in blood plasma damage to kidneys can be moderated. Also, hydration affects intrarenal hemodynamics and decreases proximal reabsorption.Clinical Risks and Usability
The main clinical concern associated with a blood fluid replacement therapy such as hemofiltration will be associated with the electrolyte composition of blood and clearance of substances with small molecular weight such as drugs.
Usability issues are concentrated around the need to maintain the supply of sterile replacement fluid (normally supplied in large 6-liter bags) connecting bags to the machine every 40 minutes and the disposal of effluent. For reference, standard bottled water fountain bottle is 19 liters. Storing and moving around this amount of volume is not a trivial task.
Limitations of Hemofiltration and Dialysis
All of the devices described prior to this point are customized general-purpose high rate “net zero” hemofiltration machines or dialysis machines. They could be used to filter out small solutes from blood for as long as it is not protein bound and is distributed in a reasonable volume. They share several common weaknesses when applied to the task of removing radiocontrast.    1. They can reduce the cumulative renal load of contrast by as much as 50% but can not eliminate it    2. They can only slightly reduce the exposure of kidneys to the initial dose of highly concentrated contrast in blood    3. They require handling, disposal and storage of large volumes of fluids    4. They require high extracorporeal blood flow that implies higher inherent risk of blood loss, larger priming volume, bigger pumps and other components    5. They could be associated with electrolyte imbalance    6. They can clear some amount of small and medium molecular weight solutes from blood